Methylphenidate (MPH, Ritalin) is a stimulant commonly prescribed for the treatment of attention- deficit/hyperactivity disorder. Intravenous (i.v.) MPH administration has become increasingly prevalent in recent years, and is an alarming trend given the lack of research on its behavioral and neurobiological consequences. The subjective effects of MPH are indistinguishable from both cocaine (COC) and amphetamine (AMPH) when administered via the same route. MPH is an AMPH analog that inhibits the dopamine (DA) and norepinephrine transporters, and although MPH is not a substrate for the transporter, it has been shown to release DA at high concentrations (Heal et al, 2009). Thus, MPH possesses DAT interactions that are similar, in part, with other psychostimulants such as COC and AMPH. The studies that have examined the effects of experimenter-delivered MPH on DA neurobiology are inconsistent, and different paradigms can cause different, sometimes opposite, effects. The proposed studies will investigate escalation of MPH intake, a paradigm that models the transition from recreational use to an addictive state. The underlying neurochemical alterations that accompany increases in intake of MPH will be identified in addition to long-term alterations DAT/psychostimulant interactions. This research will then assess the behavioral relevance of these neurochemical alterations by examining the rewarding and reinforcing effects of MPH, COC, and AMPH. Finally, using transgenic DAT over-expressing mice, a hypothesized mechanism for MPH SA-induced increases in psychostimulant neurochemical potency, reinforcing efficacy, and reward will be tested. PUBLIC HEALTH RELEVANCE: The research proposed in this NRSA addresses a major concern for public health, the neurobiological consequences of methylphenidate (MPH) abuse. Many children are prescribed MPH for the treatment of ADHD, and in addition, 4.8 million people reported abusing the easily attainable psychostimulant in 2008 (SAMHSA, 2008). There are distressingly, numerous reports and case studies documenting intravenous administration of MPH. The current models of MPH administration do not mimic human use of the compound and thus, little is known about the behavioral and neurobiological consequences of MPH abuse. By studying long access MPH self-administration, a paradigm that models the switch from abuse to addiction in humans, we will be able to determine relevant alterations that occur after extended use of the drug. In addition, by determining the effects of MPH self-administration on the rewarding and reinforcing effects of other psychostimulants, we will be able to identify the patterns that may be most dangerous in producing psychostimulant abuse in humans.